Recurrent spontaneous abortion (RSA) is a major health concern to women, affecting about 17% of couples wishing to have children. The diagnostic evaluation of RSA is extensive and complex, with many different etiologies, each causing a small proportion of the total cases. The etiologies can be grouped into five categories: anatomic, infectious, hormonal, immunological, and genetic, thereby requiring the collaborative efforts of many medical specialists. Despite such thorough (and expensive) diagnostic workups, it has been estimated that the specific cause for RSA remains unknown in 37-79% of affected women (Stephenson, Fertil. Steril. 66:24 (1996)).
It has been assumed that a large portion of idiopathic RSA is genetic in origin. To date, however, the standard genetic evaluation consists solely of parental and abortus karyotyping. This identifies parental defects, such as balanced translocations that can cause RSA, and it ascertains fetal aneuploidy, a common cause of spontaneous abortion that intrinsically has little recurrence risk. As a result, the published total "genetic" contribution to RSA is essentiually the frequency of translocations in the cohort of women with RSA, which is only about 3%. This is quite likely an underestimation, as subcytogenetic defects are almost certainly a significant cause of RSA.
It is possible that either autosomal or X-linked recessive lethal traits could cause RSA. Identification of recessive lethal traits has been difficult, as heterozygous carriers of such traits would appear phenotypically normal. A subset of lethal traits may cause an increased frquency of spontaneous abortions in carriers, if the X-linked hemizygous trait produces a clinically detectable pregnancy. Extended pedigrees in which women exhibit spontaneous abortion are available, but are difficult to analyze, because of the high population prevalence of spontaneous abortion and the assumed extensive genetic and etiologic heterogeneity. Thus, a method for clinically ascertaining carriers of autosomal lethal defects for recurrent spontaneous pregnancy loss remains problematical, although higly desirable.
There have been many efforts to characterize single genes that may cause miscarriage. However, there are approximately 100,000 genes in the human genome, which makes the search for such a single gene an almost intractable problem.
The present inventors have investigated the possibility that carriers of X-linked recessive lethal traits for recurrent spontaneous abortion manifest the molecular phenotype of nonrandom (skewed) X chromosome inactivation, and have invented a screening test for identifying and diagnosing a subset of women with recurrent spontaneous abortions. The test is based on a quantitative determination of the frequency of skewed X chromosome inactivation. This novel test, which is described below, can identify a lethal defect in a significant percentage of all of the genes in a woman. In essence, the test allows many of the lethal gene defects in the human genome to be surveyed at one time.